Accepted Manuscript

Approach to pancytopenia: Diagnostic algorithm for clinical

hematologists

Jerome Gnanaraj, Aric Parnes, Charles W. Francis, Ronald S. Go,

Clifford M. Takemoto, Shahrukh K. Hashmi

PII: S0268-960X(17)30083-8
DOI: doi:10.1016/j.blre.2018.03.001
Reference: YBLRE 526
To appear in:

Please cite this article as: Jerome Gnanaraj, Aric Parnes, Charles W. Francis, Ronald S.
Go, Clifford M. Takemoto, Shahrukh K. Hashmi , Approach to pancytopenia: Diagnostic
algorithm for clinical hematologists. The address for the corresponding author was
captured as affiliation for all authors. Please check if appropriate. Yblre(2018),
doi:10.1016/j.blre.2018.03.001

This is a PDF file of an unedited manuscript that has been accepted for publication. As
a service to our customers we are providing this early version of the manuscript. The
manuscript will undergo copyediting, typesetting, and review of the resulting proof before
it is published in its final form. Please note that during the production process errors may
be discovered which could affect the content, and all legal disclaimers that apply to the
journal pertain.
 ACCEPTED MANUSCRIPT

Approach to pancytopenia: diagnostic

algorithm for clinical hematologists
Jerome Gnanaraj M.D1 , Aric Parnes M.D2 , Charles W. Francis M.D3 , Ronald S. Go
M.D5 , Clifford M. Takemoto M.D4 , Shahrukh K. Hashmi M.D. MPH5
1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore,
Maryland, USA
2. Department of Hematology, Brigham and Women’s Hospital, Boston, Massachusetts,
USA
3. Department of Medicine, University of Rochester, Rochester, New York, USA

T
4. Division of Pediatric Hematology, Johns Hopkins University School of Medicine,

IP
Baltimore, Maryland, USA
5. Department of Medicine, Division of Hematology, Mayo Clinic, Rochester,

CR
Minnesota, USA

Corresponding Author:

US
Jerome Gnanaraj M.D.
Department of Medicine, Johns Hopkins Bayview Medical Center, Johns Hopkins
University School of Medicine, 4940 Eastern Ave, Baltimore, MD.
AN
Email: jgnanar1@jhmi.edu
M
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

Abstract
Pancytopenia is a relatively common phenomenon encountered in clinical practice.

The evaluation of a patient with pancytopenia requires a comprehensive approach

and identifying the underlying cause can be challenging given the wide range of

etiologies including drugs, autoimmune conditions, malignancies, infections,

hemophagocytosis, and inheritable conditions. Recent advances in molecular

T
IP
hematology which include genomic profiling and next-generation sequencing have

CR
helped gain major insights into various hematological conditions and can guide

diagnosing specific diseases in a shorter time at lower costs. However the approach

US
to manage patients with pancytopenia in the current era of genomics is not well
AN
defined in the literature and is widely variable in practice. Herein, we conducted a

systematic review to help devise an algorithm and management approach for

M

pancytopenia, which serves as a general consultative approach.

ED

Keywords: Pancytopenia, Aplastic anemia, NGS, megaloblastic anemia, PNH, HLH.

PT
CE
AC
 ACCEPTED MANUSCRIPT

1. Introduction
Pancytopenia is defined as a decrease in all three blood cell lines and it could

manifest with symptoms resulting from anemia, leukopenia or thrombocytopenia;

patients may however be asymptomatic. Pancytopenia may also be diagnosed

incidentally especially if mild or it can be present in some critically ill states such as

T
in sepsis. It is a relatively common phenomenon in daily medical practice and one of

IP
the most common reasons for consultation from hematologists. A survey of primary

CR
care physicians showed that about 9 out of 10 times a hematologist is consulted

when pancytopenia is found on lab studies (1). It is not a disease in itself but rather

US
a finding due to an underlying disease process affecting the bone marrow or the
AN
peripheral cell lines.
M

Although there are studies reviewing the underlying pathologies and the bone
ED

marrow findings in pancytopenia, only few are published on the approach to

pancytopenia in clinical practice (2-4). Internists, psychiatrists, obstetricians,

PT

pediatricians, and intensivists encounter the majority of cases and these are
CE

frequently referred to hematologists for further workup. The differential diagnoses

in a patient presenting with pancytopenia are broad and extensive. These are only
AC

reviewed in textbooks and a literature gap is identified regarding the management

of pancytopenia. In this review, we propose a common management approach to

pancytopenia, which is essential for hematologists who perform consultative service

in academic and community settings.

2. Methods
 ACCEPTED MANUSCRIPT

We conducted a comprehensive electronic literature search from January 1990 to

July 2016. We followed the guidelines of PRISMA statement for systematic reviews

for collecting the data. Only human studies published in English language were

included. We searched the following electronic databases: PubMed, Cochrane

Central Register of Controlled Trials and Cochrane Database of Systematic Review.

T
MeSH Terms “Pancytopenia” was combined with “Diagnosis”, “Drug Therapy”, “

IP
Epidemiology”, “Physiopathology” and “Therapy” using Boolean Language

CR
(“OR”,”AND”). We included all studies including Controlled Trials, prospective and

US
retrospective observational studies, case reports and systematic reviews. Case

reports describing pancytopenia from unusual causes were excluded.

AN
3. Results
M
ED

Our systematic search identified many causes of pancytopenia as well as a wide

variety of treatments given for conditions causing pancytopenia (Supplementary

PT

Table S1). We summarize our results below categorizing pancytopenia into three
CE

broad categories (Table 1):

 Impaired production which encompasses both bone marrow failure disorders

AC

and marrow infiltration disorders

 Peripheral destruction of different cell lines (includes splenic sequestration)

 Combination of above.

These three processes can be distinguished from one another by hematologic

testing but the crucial first steps of evaluation must include a hemogram (called
 ACCEPTED MANUSCRIPT

complete blood count [CBC] or complete picture [CP] in various countries),

peripheral blood smear, reticulocyte count and comprehensive history and a

meticulous physical examination. The reticulated platelet count or the immature

platelet fraction, though not used commonly, can also help distinguish if the

pancytopenia is due to impaired production or increased consumption.

T
IP
3.1 IMPAIRED PRODUCTION

CR
3.1.1. Acquired Aplastic anemia

US
Aplastic anemia is caused by failed hematopoiesis either due to an acquired or a

congenital cause. Several observational studies from South East Asia looking for the
AN
causes of pancytopenia by bone marrow examination point to aplastic anemia and
M

leukemia being the most common cause in children (5,6) and aplastic anemia and
ED

megaloblastic anemia among the general population (7). Congenital causes of bone

marrow failures are far less common compared to acquired causes.

PT

3.1.1.1. Idiopathic
CE

Although the cause of aplastic anemia (AA) is not clear, it is thought to be due to
AC

autoimmune destruction of pluripotent hematopoietic stem cells (HSC) by T

lymphocytes (8-11). Unregulated lymphocyte activation, impaired regulatory T

cells and increased activity of IL-17 have also been proposed as causes for the

autoimmune mechanism (12,13). Evaluation starts with a reticulocyte count and a

peripheral smear. The absolute reticulocytes are reduced and sometimes totally

absent. The peripheral blood smear may show macrocytic red blood cells with other
 ACCEPTED MANUSCRIPT

cell lines having a normal morphology. The diagnosis is established by bone marrow

aspiration and biopsy, which show reduced cellularity with absence of fibrosis and

malignant cells. In order to conclude the diagnosis of AA, besides drugs and

infections, one must exclude the absence or co-existence of paroxysmal nocturnal

hemoglobinuria (PNH), inherited bone marrow failure syndromes and

T
myelodysplastic syndrome, as the management of the latter disorders may be

IP
different. In the current genomic era, besides obtaining cytogenetics, we prefer a

CR
directed panel for use of severe AA (SAA) using the next-generation sequencing

US
(NGS), since patients with mutations in ASXL1 or DNMT3 typically have a poorer

response to immunosuppressive therapy (IST) and a greater propensity for clonal

AN
evolution development thus prompting a referral to a hematopoietic stem cell

transplant (HSCT) center. Generally, for SAA, the treatment for patients under the
M

age of 50 is by HSCT (matched related or alternative donor) but for those over 50
ED

without a fully matched donor, IST (with or without eltrombopag) may a reasonable
PT

option (14).
CE

3.1.1.2. Drugs and Radiation

AC

Many drugs can cause aplastic anemia. Toxins like benzene, chemotherapeutic

drugs, NSAIDs, antiepileptic drugs, steroids, and chloramphenicol are commonly

known to cause AA. The mechanism of aplasia is either by direct toxic effect on the

stem cells or from autoimmune mechanisms. Studies have shown that activity of P –

Glycoprotein in the cells is decreased among patients with AA (15). Reduced activity

of P – Glycoprotein can cause accumulation of the drugs in the cytoplasm leading to

 ACCEPTED MANUSCRIPT

toxic levels. In some occasions, as in the idiosyncratic reaction seen in

chloramphenicol, effects of the drugs on the bone marrow can be irreversible, which

led consequently to a marked decline in its use. Most conventional

chemotherapeutic agents cause pancytopenia by direct bone marrow toxicity.

Specifically, fluropyrimidines such as flurouracil and capecitabine can cause severe

T
and sometimes fatal toxicities if administered in patients with deficiency of

IP
dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism o f uracil

CR
and thymine. Biological agents such as inhibitors of TNF and IL-6 can cause

US
neutropenia but pancytopenia is rare.

Alcohol abuse can affect all the three cell lines. There are several ways how alcohol
AN
can cause these hematological toxicities. Alcohol can cause direct bone marrow
M

toxicity as evidenced by hypoplastic bone marrow in some of these patients. Excess

ED

alcohol consumption can also increase the absorption of iron from the

gastrointestinal tract leading to iron overload, which in turn can contribute to

PT

hepatitis and cirrhosis. Other possible mechanisms are interference with folate
CE

absorption and acetaldehyde forming adducts with cell membrane phospholipids

(16,17).
AC

Radiation therapy can also damage the HSC and result in pancytopenia (18). Bone

marrow hypoplasia develops at cumulative doses greater than 5 Gy. The cytopenia

reaches a nadir 1 to 4 weeks after the treatment and can persist for months. Having

a more ventral exposure and sparing the dorsal bone marrow (in spine, ribs and

pelvis) during the radiation might protect a significant percent of bone marrow
 ACCEPTED MANUSCRIPT

activity. This is an important aspect of radiation biology for hematologists, as some

cancer patients (particularly gynecologic cancers) receive radiation to the pelvic

bones and may develop profound and prolonged pancytopenia but it is generally

reversible.

3.1.1.3. Infections

T
IP
Infections, mostly viral, are another cause of cytopenias in both adults and children.

CR
A prospective study among children by Alexandropoulo et al showed that an

US
infectious agent was identified in about 63.8% of febrile non-cancer patients with

cytopenias (19). About 45% of these were due to viral infection and the cytopenia
AN
was transient in 83% of the cases. Parvovirus B19 can directly attack

proerythroblasts whereas aplasia caused by other viruses is usually due to T cell

M

mediated mechanisms (20), however, parvovirus more commonly causes anemia

ED

only and patients with chronic hemolytic anemias are usually the most vulnerable.
PT

The pancytopenia caused by the viruses is usually transient and reversible with

resolution of the infection. In a hematology consultation for pancytopenia, if a viral

CE

infection is suspected, then the common agents which should be evaluated include
AC

infectious hepatitis (Hepatitis A, B, and C), cytomegalovirus (CMV), Epstein-Barr

virus (EBV), Human HerpesVirus 6 (HHV-6), Parvovirus B19, and human

immunodeficiency virus (HIV). Pancytopenia associated with hepatitis is more

severe than that associated with other infections and is less likely to resolve

spontaneously (21). Hepatitis associated AA (HAA) is a distinct variant of aplastic

anemia, which occurs after an episode of acute hepatitis. The mechanism is thought
 ACCEPTED MANUSCRIPT

to be due to T cell mediated cytokine release. Leishmaniasis and tuberculosis can

rarely result in chronic bone marrow suppression via direct affect and should be

tested for in the countries where these diseases are endemic.

3.1.2. Congenital Aplastic anemia

T
A multitude of inheritable causes of AA have been discovered. A better terminology

IP
for this condition is inherited bone marrow failure syndromes (BMF) since “anemia”

CR
is not the only presentation, and in fact, the majority of the patients suffer from

US
profound pancytopenia with neutropenia being the most important culprit to which

these patients can succumb. Our search yielded that the most common causes of
AN
inherited BMF syndromes are Fanconi’s Anemia (FA), Dyskeratosis congenita (DC),

GATA2 associated syndromes (e.g. Emberger and MonoMAC syndromes), and

M

Shwachman-Diamond syndrome (SDS). Congenital amegakaryocytic

ED

thrombocytopenia (CAMT) rarely leads to pancytopenia and most patients are

PT

either transplanted before this or they die of bleeding if they are not transplanted

soon enough. The associated clinical findings help distinguish the different types
CE

(Table 2), although they are not present consistently due to extreme variability in
AC

phenotypic expression. These disorders are usually diagnosed in early childhood

but about up to 25 % of patients may have cryptic presentations and are not

diagnosed until adulthood. However, statistically speaking, congenital aplasia is far

less common than the acquired aplastic anemia, even in children. In a large study of

myelodysplastic syndrome (MDS) patients undergoing allogeneic HSCT who were

enrolled in the Center for International Blood and Marrow Transplant Research
 ACCEPTED MANUSCRIPT

Repository (CIBMTR), targeted mutational analysis on samples obtained pre-HSCT

was performed, and 4% of the young patients were found to have compound

heterozygous mutations in the SDS–associated SBDS gene, thus underscoring the

importance of appropriate genomic testing for young patients with pancytopenia

even if they present with MDS (22).

T
IP
Telomere length measurement for DC and chromosomal breakage (and

CR
diepoxybutane [DEB] or mitomycin C) testing for FA should be performed for

suspected cases from peripheral blood (peripheral blood is preferred over bone

US
marrow aspirate for these tests). The leukocyte telomere length measurement

(ideally via Flow-FISH, but qPCR may suffice) is generally expensive and may not be
AN
readily available in all institutions, and efforts must be made to utilize this test only
M

in strongly suspected cases for the sake of a cost-effective approach.

ED

Once the diagnosis of inherited BMF syndromes is made, gene sequencing and
PT

Human leukocyte antigen (HLA) typing of the patient, and the HLA typing of the

family members should be done as early as possible which is crucial for

CE

management and for HSCT (23,24).

AC

Unlike idiopathic SAA, inheritable BMF syndromes should not be treated with IST

and immediate referral to a HSCT center should be made which is the only known

curative therapy. Since the therapy of idiopathic AA is different from BMF

syndromes, it is crucial that hematologists make correct diagnosis – thus if the

chromosomal breakage studies are negative i.e. the report indicates “no growth”,

then further testing via skin biopsy (for dermal fibroblasts) should be performed in
 ACCEPTED MANUSCRIPT

strongly suspected cases of inheritable BMF syndromes.

3.1.3. Bone Marrow infiltrative disorders

3.1.3.1. Primary myelofibrosis

Primary myelofibrosis (PMF) is one of the chronic myeloproliferative neoplasms

T
IP
(MPN) characterized by clonal proliferation of abnormal megakaryocytes. Patients

CR
usually present with pancytopenia, extreme fatigue and an enlarged spleen and liver

due to extramedullary hematopoiesis. The peripheral smear shows

US
leukoerythroblastic reaction (myelophthisic smear), with teardrop cells, left-shifted

(immature) white blood cells (WBC) and nucleated RBCs. Circulating CD34+ cells
AN
can help in distinguishing this entity from other forms of myeloproliferative
M

disorders (25); however a BMB is required for definitive diagnosis in order to fulfill
ED

the current World Health Organization’s criteria for MPN. Bone marrow aspiration

usually is difficult yielding a dry tap, and bone marrow biopsy is necessary for
PT

demonstrating reticulin fibrosis (26). Patients with high and intermediate risk PMF
CE

according to the DIPSS plus score (Dynamic International Prognostic Scoring

System) should be referred urgently for HSCT (27), since this procedure remains the
AC

only potentially curative therapy for PMF up-to-date. In other risk groups of PMF,

management is focused on supportive care.

3.1.3.2. Systemic diseases infiltrating bone marrow

Diseases that metastasize to the bone marrow may cause pancytopenia by

interfering with the production of the blood cells. Leukemia, lymphoma, fibrosis,
 ACCEPTED MANUSCRIPT

autoimmune and granulomatous diseases typically infiltrate the marrow and cause

profound pancytopenia. In the pediatric population, metastatic neuroblastoma very

commonly also invades the marrow and many children present with pancytopenia

as the only symptom at first. Acute leukemias infiltrate the marrow more rapidly

than chronic leukemias. Acute lymphoblastic leukemia (ALL) is one of the most

T
common cancers of childhood, whereas acute myeloid leukemia (AML) is the most

IP
common acute leukemia affecting adults (28). They are usually diagnosed with

CR
blasts on the peripheral smear, which is typically the common reason to consult a

US
hematologist. Then a bone marrow biopsy (BMB) and aspirate, flow cytometry,

immunophenotyping and cytogenetic studies are indicated for diagnosis and

AN
prognosis. The BMB should be performed early in suspected cases of acute

leukemias given the aggressive biology of the disease. An exception to this rule of
M

essential testing with BMB is elderly patients with severe comorbidities who are
ED

unable to undergo any kind of aggressive chemotherapy and the diagnosis is clear
PT

via peripheral blood testing. Occasionally in such patients, palliation can be started

without a BMB since the current pathology techniques (particularly flow cytometry)
CE

can usually differentiate between ALL and AML. All other eligible patients
AC

(especially below the age of 70 years), should be referred to a HSCT center upon

diagnosis and HLA typing should be obtained since allogeneic HSCT currently

remains the only potentially curative option in high risk, refractory or relapsed

patients. If the treating or consulting hematologist has any doubts about the

candidacy for HSCT for a leukemia patient, it is best to make the referral so that the

transplant physician can decide about the candidacy based on the baseline health
 ACCEPTED MANUSCRIPT

and the disease characteristics.

Genetic testing through next-generation sequencing is also making significant

impact in the diagnostic work-up of acute leukemias since mutations can provide

prognostic as well as therapeutic information from precision medicine perspective

e.g. such as who requires transplant and for targeted therapies. Plasma cell

T
IP
dyscrasias (both myeloma and amyloidosis), hairy cell leukemia (HCL), and other

CR
metastatic diseases (e.g. carcinomas) can also infiltrate the bone marrow. HCL

typically presents with massive splenomegaly and pancytopenia, and consulting

US
hematologist can look at the peripheral blood smear preferably with Romanowsky-

stain to evaluate for this entity. A “dry tap” during BMB further points towards HCL,
AN
and in the current decade, hematologists should NOT order the “TRAP stain” since
M

flow cytometry can provide adequate information for the diagnosis of HCL and is
ED

technically less challenging than the TRAP staining. Large granular Lymphocyte (

LGL) leukemia is a clonal disorder affecting the large granular lymphocytes which
PT

can cause marrow infiltration leading to cytopenia. The diagnosis is based on

CE

immunophenotypic analysis of the peripheral smear but bone marrow

biopsy/aspirate may be required in some cases. Solid tumors that frequently

AC

metastasize to the bone marrow in adults are prostate, breast and lung.(29)

Other bone marrow infiltrative disorders include autoimmune myelofibrosis, which

can be related to lupus (30), however many autoimmune causes can result in

infiltration. It is generally rare but occasionally hematologists are consulted for

inpatients suffering from autoimmune disease flares. Most of the autoimmune

 ACCEPTED MANUSCRIPT

cytopenias are steroid responsive and initial treatment includes corticosteroid

dosages in the range of 0.5-1 mg/kg/day. Granulomatous diseases like miliary TB

and sarcoidosis and metabolic disorders like Gaucher disease can also cause

pancytopenia by causing intense marrow infiltration (31). Generally the clues

towards a diagnosis of Gaucher disease in a pancytopenia patient are massive

T
hepatosplenomegaly, bone disease (avascular necrosis [AVN], osteoporosis, bone

IP
pain, osteolytic fractures), neurologic symptoms (seizures, neuropathy and

CR
parkinsonism), and growth retardation. Some cases may be diagnosed in adulthood

US
and thus a high degree of clinical suspicion is required by the astute hematologist.

The hematopathologist or hematologist should carefully evaluate the BMB for the
AN
large macrophages laden with cereberosides. Mutational analysis and biochemical

enzyme analysis follows next and then immediate referral to a HSCT center with
M

metabolic diseases expertise should be made for consideration of HSCT and/or

ED

enzyme replacement therapy. Patients with Gaucher type 2 disease don’t respond
PT

well to enzyme replacement therapy and are usually treated with HSCT.
CE

3.1.4. Nutritional Deficiencies

AC

Folate and vitamin B12 deficiencies can cause megaloblastic anemia. Though

anemia and thrombocytopenia are the common features, they could present with

pancytopenia as well. In a cross sectional observational study in Pakistan,

pancytopenia was found in 70% of patients with megaloblastic anemia (32). B12

deficiency is most likely due to ineffective absorption whereas folate deficiency is

due to inadequate dietary intake and alcoholism. Since the fortification of food with
 ACCEPTED MANUSCRIPT

folic acid in the late 1990s, folate deficiency has been extremely rare in the United

States (US) and is seen mostly in patients who are malnourished (33). However,

folate deficiency has not been eradicated in many regions of the world. B12 and

folate deficiency should be suspected in any patient with unexplained pancytopenia,

macrocytosis, hypersegmented neutrophils, and unexplained neurological signs and

T
symptoms. Diagnosis is by measurement of serum B12 levels, folate levels and also

IP
levels of their metabolic intermediates, which accumulate in these deficiencies.

CR
Homocysteine accumulates in both folate and B12 deficiencies, while methylmalonic

US
acid accumulates only in B12 deficiency. When the diagnosis is not clear, therapeutic

trials with B12 are needed. Bone marrow examination is not needed to diagnose
AN
B12 and folate deficiency. In the current era of explosive growth of bariatric

surgeries, hematologists should be well prepared to deal bariatric surgery induced

M

cytopenias, since both sleeve gastrectomy and Roux-en-Y gastric bypass can cause
ED

vitamin B12 deficiency (34).

PT

Copper deficiency commonly causes anemia and leukopenia. However, it can rarely
CE

also cause pancytopenia. The common causes of acquired copper deficiency are

gastric surgery, malabsorption syndromes, excessive zinc intake and chelation

AC

therapy (35). Bone marrow examination shows cytoplasmic vacuolization in the

erythroid and myeloid precursors (36). Serum copper and ceruloplasmin levels

should help in the diagnosis.

3.1.5. Myelodysplastic syndrome

Myelodysplastic syndrome is a clonal stem cell disorder characterized by dysplastic

 ACCEPTED MANUSCRIPT

bone marrow. It usually affects people over the age of 65 with a male predominance

(37), however, therapy related myeloid neoplasms which constitute both AML and

MDS can occur at any age after leukemogenic exposures (chemotherapy or

radiation). The peripheral blood smear may show Pelger Huet – like anomaly in

neutrophils (a bilobed nucleus in the neutrophil connected by a thin isthmus) and

T
immature myeloid or erythroid cells. Hypogranulated neutrophils can also be

IP
present in the smear. Bone marrow aspirate is also essential for diagnosis.

CR
Diagnosis is made by the presence of the following features –decrease in one or

US
more of the blood elements without another cause, morphologic evidence of

dysplasia in the peripheral smear, bone marrow aspirate and biopsy and blast forms
AN
less than 20% of the total cell count of the bone marrow aspirate.

Immunophenotyping studies may show a decrease in the number of myeloid

M

maturation antigens or presence of new antigens, which are not normally present.
ED

Flow cytometry and immunophenotyping also helps in differentiating MDS from

PT

other cytopenias in post cancer therapy patients (38).

CE

Although diagnostic criteria have yet to incorporate the genetic underpinnings of

MDS except for the 5q minus syndrome, MDS has witnessed significant advances in
AC

mutation analysis via NGS. At many institutions, this has become as common as a

bone marrow biopsy, and is providing valuable prognostic information. Frequently,

MDS-associated mutations are found, such as SF3B1, TET2, SRSF2, DNMT3A, and

ASXL1. However, patients may not yet fulfill MDS criteria, so they have been given

the new diagnosis of CHIP (clonal hematopoiesis of indeterminate potential) or

CCUS (clonal cytopenias of undetermined significance), both precursors to MDS,

 ACCEPTED MANUSCRIPT

itself a precursor to acute leukemia (39,40).

Treatment is supportive care, chemotherapy, and/or HSCT based on a prognosis

score called the “Revised International Prognosis Scoring System” (IPSS-R). Patients

who score less than 2 points are treated either with supportive care or low intense

chemotherapy or immunosuppressive therapy. For patients with higher risk

T
IP
(greater than 4 points) treatment should ideally include HSCT in eligible patients.

CR
For those with intermediate risk, the treatment should be based on patient

preferences and other individual pre-existing conditions. Thus it is imperative that

US
the diagnosis of MDS should prompt referral to a transplant center unless the

patient is very old or suffers from many comorbid conditions.

AN
MDS in childhood is a distinct entity with a different WHO classification. MDS is rare
M

in childhood and has a poor prognosis without HSCT. Refractory cytopenia of

ED

childhood is the most common subtype of MDS in children and monosomy 7/del 7q
PT

is the most frequently seen clonal abnormality. The main treatment is focused on

early HSCT as there is risk for relapse and clonal evolution with immunosuppressive
CE

treatment (41), thus referral to a transplant center early in the course is advised.
AC

Mutations in the GATA2 gene can cause familial MDS/ AML. GATA2 belongs to a

family of transcription factors that are critical regulators of gene expression in

hematopoiesis (42). Different kinds of mutations including missense mutation,

nonsense mutation, large genomic rearrangements can cause GATA2 deficiency. In

addition to Familial MDS and AML it is also associated with monocytopenia, B and

NK cell lymphopenia, increased susceptibility to non-tuberculosis mycobacterial

 ACCEPTED MANUSCRIPT

and viral infections. Early diagnosis with genetic testing is crucial for management,

preventive care and screening of other family members (43)

3.2. PERIPHERAL DESTRUCTION

3.2.1. Autoimmune-mediated pancytopenia

T
IP
SLE can present with pancytopenia when all the three cell lines are affected,

CR
however it is less common than isolated cytopenias. In addition to immune-

mediated process, multiple other factors contribute to cytopenias in lupus patients.

US
Pancytopenia in SLE could be due to medications, infections, splenomegaly,

autoimmune myelofibrois and rarely HLH/ MAS (44). Most lupus patients with
AN
pancytopenia need a bone marrow biopsy to rule out other causes. Patients with
M

autoimmune rheumatological disorders like rheumatoid arthritis, psoriasis, SLE are

ED

at increased risk for lymphoproliferative disorders and it is important to exclude

underlying malignancies like lymphoma while evaluating these patients (45-47).

PT

Autoimmune cytopenias are also seen in autoimmune lymphoproliferative

CE

syndrome (ALPS) and common variable immunodeficiency disease (CVID).

AC

Autoimmune hemolytic anemia and immune thrombocytopenia are more common

than autoimmune neutropenia (AIN) in both ALPS and CVID. All cytopenias

including AIN are more common in CVID in children compared with adults. Since

these patients also have splenomegaly, it is important to differentiate if the

cytopenias are related to autoimmune condition rather than hypersplenism.

Autoimmune cytopenias can also occur with chronic lymphocytic leukemia (CLL). It
 ACCEPTED MANUSCRIPT

could present as autoimmune hemolytic anemia, thrombocytopenia or pure red cell

aplasia (PRCA). The first line treatment for these autoimmune diseases is

corticosteroids. In patients not responding to steroid treatment, chemo-

immunotherapy and splenectomy are reasonable alternatives (48, 49).

Blood cytopenias, which remain undiagnosed despite adequate evaluation, are

T
IP
classified as idiopathic cytopenia of undetermined significance (ICUS). They should

CR
not have any known clonal disorders. ICUS is not a specific disease per se and they

usually resolve over time or are found to be due to a non-myeloid malignancy,

US
nutritional disorder or immune-mediated disorder. A study by Liu et al has shown at

least some of these immune-mediated cytopenias might be due to antibodies

AN
targeting the EPO receptor (50).
M

3.2.2. Splenic Sequestration

ED

Hypersplenism is characterized by splenomegaly, a decrease in one or more blood

PT

elements with a subsequent increase in their bone marrow precursors and

CE

correction of the cytopenia by splenectomy (51). Hypersplenism causes

pancytopenia by splenic sequestration and in some cases by hemolysis (52).

AC

Patients can present with pain or fullness in the left upper quadrant, abdominal

distension or referred pain to the shoulder. The causes are numerous. Cirrhosis,

congestive heart failure, malignancies like leukemia/ lymphoma,

hemoglobinopathies and infections are some of the common ones. The diagnostic

approach should begin with imaging studies like CT of the chest and abdomen

looking for malignancies and signs of portal hypertension. Splenectomy should be

 ACCEPTED MANUSCRIPT

considered if appropriate, although splenectomy alone is not curative. Long-term

complications of splenectomy include an increased risk for infections and

thromboembolism and these should be considered while making a decision to

perform a splenectomy.

3.3. COMBINATION OF IMPAIRED PRODUCTION AND PERIPHERAL

T
IP
DESTRUCTION

CR
3.3.1. Paroxysmal Nocturnal Hemoglobinuria

US
PNH is a rare acquired stem cell disorder characterized by mutation in the PIGA

gene resulting in defective cell membrane leading to hemolysis, pancytopenia and

AN
thrombosis. PIGA protein is necessary for the synthesis of GPI anchor, which helps a
M

subset of cell proteins (CD55 and CD59) adhere to the plasma membrane. Lack of
ED

this GPI anchor ultimately leads to complement-mediated intravascular hemolysis.

The mechanism of thrombosis is unclear. Patients usually present with symptoms of

PT

hemolytic anemia and thrombosis in atypical locations. The RBC breakdown causes
CE

release of hemoglobin pigments into the urine, which presents as dark red colored

urine in the early morning. If initial blood tests show negative direct coombs test
AC

along with intravascular hemolysis, then PNH should be suspected. Confirmato ry

test is flow cytometry with FLAER (Fluorescent AERolysin – a reagent which binds

to the GPI anchor which is defective in PNH) (53). Treatment of classical PNH is with

eculizumab or HSCT. Thromboembolism is a major cause of death and patients

should be monitored for signs and symptoms of venous thrombosis and treated

promptly (54).
 ACCEPTED MANUSCRIPT

3.3.2. Hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening disorder, which can

present with pancytopenia. It can be either familial or sporadic, caused by various

triggers like infections, malignancies, rheumatologic and immunodeficiency

syndromes (55). It is characterized by tissue and cell destruction due to activation of

T
IP
macrophages (histiocytes) and lymphocytes from defective down regulation (56).

CR
HLH presents with multiple organ failure and initial evaluation should include

complete blood count with differential, coagulation studies, fibrinogen, serum

US
ferritin (usually >1000 mg/mL), liver function tests and triglycerides, soluble CD25.

Biopsies often reveal red cell ingestion by histiocytes (hemophagocytosis). Familial

AN
HLH (FLH) is caused by mutation affecting either one of the FLH loci or a gene
M

causing one of several congenital immunodeficiency syndromes. The mutations

ED

usually target one of the components of the perforin mediated cytotoxic pathway.

Treating the underlying conditions may lead to improvement of HLH but patients
PT

who deteriorate need HLH specific treatment. Untreated patients usually have a
CE

very high mortality rate and timely diagnosis is often a challenge due to its atypical

presentation (57). It is a frequent but often overlooked complication of sick patients

AC

who are hospitalized especially in the intensive care units (commonly due to

infections), therefore a consulting hematologist must be aware of the current

criteria for diagnosis and management paradigm which may include prompt

administration of corticosteroids and/or chemotherapy (etoposide).

4. SUMMARY
 ACCEPTED MANUSCRIPT

Pancytopenia is a clinical entity representing a wide array of medical conditions.

The first step in the management of pancytopenia involves identifying the

underlying cause and providing supportive care till the pancytopenia is resolved. A

complete history and physical examination usually helps in narrowing down the

cause, which could then lead to further specific diagnostic studies. We have devised

T
an algorithm (Figure 1) to guide physicians in diagnosing pancytopenia. Identifying

IP
whether the pancytopenia is caused by a production disorder or a consumption

CR
disorder or a combination of both is a key step in both diagnosing the cause and for

US
management of the patient.

5. PRACTICE POINTS
AN
 Next-generation sequencing has made genome sequencing faster and more
M

affordable, which helps to diagnose many congenital causes of aplastic

ED

anemia
PT

 It is vital to identify disorders which require HSCT early in the course of

management as these patient might need to be transferred to Transplant

CE

centers
AC

 Although nutritional cause of pancytopenia has decreased due to folate

fortification of food, alcohol abuse, malabsorption syndromes and bariatric

surgeries can all lead to pancytopenia

6. RESEARCH AGENDA

Identifying whether the pancytopenia is caused by impaired production or

 ACCEPTED MANUSCRIPT

increased destruction helps narrow down from a wide variety of disorders causing

pancytopenia and an algorithm such as the one presented here helps in determining

the specific cause.

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Ayas Mouhab for his time and contribution to

T
this article.

IP
CONFLICT OF INTEREST

CR
The authors report no conflict of interest.

US
AN
M
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

Figure 1. General management approach and algorithm to help diagnose the cause of pancytopenia.

A comprehensive initial workup helps to differentiate the underlying mechanism of pancytopenia

and a more focused testing help identify the specific cause.

T
IP
CR
US
AN
M
ED
PT
CE
AC
 ACCEPTED MANUSCRIPT

References
1. Abel GA, Friese CR, Neville BA, Wilson KM, Hastings BT, Earle CC, et al.
Referrals for suspected hematologic malignancy: a survey of primary care
physicians. Am J Hematol. 2012; 87:634-6.
2. Weinzierl EP, Arber DA. The Differential Diagnosis and Bone Marrow Evaluation
of New-Onset Pancytopenia. Am J Clin Pathol 2013; 139:9-29.
3. Devitt KA, Lunde JH, Lewis MR. New onset pancytopenia in adults: a review of
underlying pathologies and their associated clinical and laboratory findings. Leuk
Lymphoma 2014; 55:1099-105.

T
4. Savage DG, Allen RH, Gangaidzo IT, Levy LM, Gwanzura C, Moyo A, et al.

IP
Pancytopenia in Zimbabwe. Am J Med Sci 1999; 317:22-32.
5. Memon S, Shaikh S, Nizamani MA. Etiological spectrum of pancytopenia based on

CR
bone marrow examination in children. J Coll Physicians Surg Pak 2008; 18:163-7.
6. Gupta V, Tripathi S, Tilak V, Bhatia BD. A study of clinico-haematological profiles
of pancytopenia in children. Trop Doct 2008; 38:241-3.

US
7. Jha A, Sayami G, Adhikari RC, Panta AD, Jha R. Bone marrow examination in cases
of pancytopenia. JNMA J Nepal Med Assoc 2008; 47:12-7.
8. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and
AN
treatment of aplastic anemia. Blood. 2006; 108:2509.
9. Young NS. Acquired aplastic anemia. Ann Intern Med 2002; 136:534.
10. Solomou EE, Wong S, Visconte V, Gibellini F, Young NS. Decreased TCR zeta-
M

chain expression in T cells from patients with acquired aplastic anaemia.

Br J Haematol 2007; 138:72.
11. Yu H, Zhang J, Fu R, Liu H, Wang H, Ding K, et al. Increased frequency of bone
ED

marrow T follicular helper cells in patients with immune-related pancytopenia. Clin

Dev Immunol. 2013; 2013:730450.
12, Shi J, Ge M, Lu S, Li X, Shao Y, Huang J, et al. Intrinsic impairment of
PT

CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia. Blood. 2012;

120:1624-32.
CE

13. Gu Y, Hu X, Liu C, Qv X, Xu C. Interleukin (IL)-17 promotes macrophages to

produce IL-8, IL-6 and tumour necrosis factor-alpha in aplastic anemia. Br J
Haematol. 2008;142:109-14.
AC

14. Kao SY, Xu W, Brandwein JM, Lipton JH, Messner HA, Minden MD, et al. Outcomes
of older patients (> or = 60 years) with acquired aplastic anemia treated with
immunosuppressive therapy. Br J Haematol 2008; 143:738.
15. Calado RT, Garcia AB, Gallo DA, Falcão RP. Reduced function of the multidrug
resistance P-glycoprotein in CD34+ cells of patients with aplastic anaemia. Br J
Haematol 2002; 118:320.
16. Girard DE, Kumar KL, McAfee JH. Hematologic effects of acute and chronic
alcohol abuse. Hematol Oncol Clin North Am. 1987; 1:321.
17. Niemelä O, Parkkila S. Alcoholic macrocytosis--is there a role for acetaldehyde
and adducts? Addict Biol. 2004; 9:3-10.
 ACCEPTED MANUSCRIPT

18. Weisdorf D, Chao N, Waselenko JK, Dainiak N, Armitage JO, McNiece I, et al. Acute
radiation injury: contingency planning for triage, supportive care, and
transplantation. Biol Blood Marrow Transplant 2006; 12:672–682.
19. . Alexandropoulou O, Kossiva L, Giannaki M, Panagiotou J, Tsolia M, Karavanaki
K. The epidemiology, clinical course and outcome of febrile cytopenia in children.
Acta Paediatr 2015; 104:112-8.
20. Ikawa Y, Nishimura R, Kuroda R, Mase S, Araki R, Maeba H, et al. Expansion of a
liver-infiltrating cytotoxic T-lymphocyte clone in concert with the development of
hepatitis-associated aplastic anaemia. Br J Haematol 2013; 161:599-602.
21. Brown KE, Tisdale J, Barrett AJ, Dunbar CE, Young NS. Hepatitis-associated

T
aplastic anemia. N Engl J Med. 1997; 336:1059-64.

IP
22. Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic
Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J

CR
Med. 2017; 376:536-547.
23. Meldrum C, Doyle MA, Tothill RW.Next-Generation Sequencing for Cancer
Diagnostics: a Practical Perspective. Clin Biochem Rev 2011; 32:177-95.

US
24. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing.
N Engl J Med 2014; 370:2418-25.
25. Barosi G, Viarengo G, Pecci A, Rosti V, Piaggio G, Marchetti M, et al. Diagnostic
and clinical relevance of the number of circulating CD34(+) cells in myelofibrosis
AN
with myeloid metaplasia. Blood 2001; 98:3249.
26. Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, et al. Proposals
and rationale for revision of the World Health Organization diagnostic criteria for
M

polycythemia vera, essential thrombocythemia, and primary myelofibrosis:

recommendations from an ad hoc international expert panel. Blood 2007;
ED

110:1092-7.
27. Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al.
DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary
PT

myelofibrosisthat incorporates prognostic information from karyotype, platelet

count, and transfusion status. J Clin Oncol. 2011; 29:392-7.
28. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States
CE

by subtype and demographic characteristics, 1997–2002. Cancer Causes Control

2008; 19:379–390.
29. Anner RM, Drewinko B. Frequency and significance of bone marrow involvement by
AC

metastatic solid tumors. Cancer. 1977; 39:1337–1344

30. Paquette RL, Meshkinpour A, Rosen PJ. Autoimmune myelofibrosis. A steroid-
responsive cause of bone marrow fibrosis associated with systemic lupus
erythematosus. Medicine (Baltimore) 1994; 73:145-52.
31. Mert A, Bilir M, Tabak F, Ozaras R, Ozturk R, Senturk H et al. Miliary tuberculosis:
clinical manifestations, diagnosis and outcome in 38 adults. Respirology 2001;
6:217–224.
32. Khattak MB, Ismail M, Marwat ZI, Khan F. Frequency and characterisation of
pancytopenia in megaloblastic anaemia. J Ayub Med Coll Abbottabad. 2012; 24:53-
55.
33. Crider KS, Bailey LB, Berry RJ. Folic Acid Food Fortification—Its History, Effect,
Concerns, and Future Directions. Nutrients. 2011; 3:370-384.
 ACCEPTED MANUSCRIPT

34. Kwon Y, Kim HJ, Lo Menzo E, Park S, Szomstein S, Rosenthal RJ et al. Anemia,
iron and vitamin B12 deficiencies after sleeve gastrectomy compared to Roux -en-Y
gastric bypass: a meta-analysis. Surg Obes Relat Dis. 2014; 10:589-97.
35. Huff JD, Keung YK, Thakuri M, Beaty MW, Hurd DD, Owen J, et al. Copper
deficiency causes reversible myelodysplasia. Am J Hematol. 2007; 82: 625–630.
36. Willis MS, Monaghan SA, Miller ML, McKenna RW, Perkins WD, Levinson BS, et al
Zinc-induced copper deficiency: a report of three cases initially recognized on bone
marrow examination. Am J Clin Pathol. 2005 ;123:125-31.
37. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and
survival in the United States. Cancer 2007; 109:1536.

T
38. Tang G, Jorgensen LJ, Zhou Y, Hu Y, Kersh M, Garcia-Manero G, et al. Multi-color

IP
CD34⁺ progenitor-focused flow cytometric assay in evaluation of myelodysplastic
syndromes in patients with post cancer therapy cytopenia. Leuk Res 2012; 36:974-8.

CR
39. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al.
Clonal hematopoiesis of indeterminate potential and its distinction from
myelodysplastic syndromes. Blood 2015; 126:9-16.

US
40. Malcovati L, Cazzola M. The shadowlands of MDS: idiopathic cytopenias of
undetermined significance (ICUS) and clonal hematopoiesis of indeterminate
potential (CHIP). Hematology Am Soc Hematol Educ Program 2015; 2015:299-307.
41. Yoshimi A, van den Heuvel-Eibrink MM, Baumann I, Schwarz S, Simonitsch-
AN
Klupp I,de Paepe P et al. Comparison of horse and rabbit antithymocyte globulin in
immunosuppressive therapy for refractory cytopenia of childhood. Haematologica
2014; 99:656-63.
M

42. Bresnick EH, Katsumura KR, Lee HY, Johnson KD, Perkins AS. Master regulatory
GATA transcription factors: mechanistic principles and emerging links to
ED

hematologic malignancies. Nucleic Acids Res 2012; 40:5819-31.

43. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2
deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity.
PT

Blood 2014:123:809-21.
44. Velo-García A, Castro SG, Isenberg DA. The diagnosis and management of the
haematologic manifestations of lupus. J Autoimmun. 2016; 74:139-160.
CE

45. Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al.

Association of chronic inflammation, not its treatment, with increased lymphoma
risk in rheumatoid arthritis. Arthritis Rheum. 2006; 54:692-701.
AC

46. Margolis D, Bilker W, Hennessy S, Vittorio C, Santanna J, Strom BL. The risk of
malignancy associated with psoriasis. Arch Dermatol. 2001; 137:778-83.
47. Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma
development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;
165:2337-44.
48. Rossignol J, Michallet AS, Oberic L, Picard M, Garon A, Willekens C, et al.
Rituximab-cyclophosphamide-dexamethasone combination in management of
autoimmune cytopenias associated with chronic lymphocytic leukemia.
Leukemia 2011; 25:473-8.
49. Hodgson K, Ferrer G, Pereira A, Moreno C, Montserrat E. Autoimmune cytopenia
in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol 2011;
 ACCEPTED MANUSCRIPT

154:14-22.
50. Liu H, Fu R, Li L, Ding K, Wang Y, Wang H, et al. Erythropoietin Receptors and IgG
Autoantibody Expression on Nucleated Erythrocytes in Some Cases of Immuno -
Related Pancytopenia. Clin Lab 2015; 61:693-8.
51. Jandl JH, AsterRH, Forkner CE, Fisher AM, and Vilter RW. Splenic pooling and
the pathophysiology of hypersplenism. Trans Am Clin Climatol Assoc 1967; 78:9-27.
52. Jandl JH, Aster RH. Increased splenic pooling and the pathogenesis of
hypersplenism. Am J Med Sci 1967; 253:383–398.
53. Brodsky RA, Mukhina GL, Li S, Nelson KL, Chiurazzi PL, Buckley JT, et al.
Improved detection and characterization of paroxysmal nocturnal hemoglobinuria

T
using fluorescent aerolysin. Am J Clin Pathol 2000; 114:459.

IP
54. Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal
hemoglobinuria and the risk of venous thrombosis: review and recommendations

CR
for management of the pregnant and nonpregnant patient. Haemostasis 2000;
30:103.
55. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat

US
hemophagocytic lymphohistiocytosis. Blood. 2011; 118:4041-4052.
56. Filipovich A, McClain K, Grom A. Histiocytic disorders: recent insights into
pathophysiology and practical guidelines. Biol Blood Marrow
Transplant. 2010;16:S82-9.
AN
57. Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis.
Arch Dis Child. 2011; 96:688-93.
58. Kurzrock R, Talpaz M, Estrov Z, Rosenblum MG, Gutterman JU. Phase I study of
M

recombinant human interleukin-3 in patients with bone marrow failure. J Clin

Oncol 1991; 9:1241-50.
ED

59. Huić D, Ivancević V, Aurer I, Dodig D, Nemet D, Labar B, et al. Bone marrow
immunoscintigraphy in haematological patients with pancytopenia: preliminary
results. Nucl Med Commun. 2002; 23:757-63.
PT

60. Svahn BM, Remberger M, Myrbäck KE, Holmberg K, Eriksson B, Hentschke P, et

al. Home care during the pancytopenic phase after allogeneic hematopoietic stem
cell transplantation is advantageous compared with hospital care. Blood. 2002;
CE

100:4317-24.
61. Zhu X, Guan J, Xu J, Wei J, Jiang L, Yin J, et al. Pilot study using tacrolimus rather
than cyclosporine plus antithymocyte globulin as an immunosuppressive therapy
AC

regimen option for severe aplastic anemia in adults. Blood Cells Mol Dis 2014;
53:157-60.
62. Morishita S, Kaida K, Setogawa K, Kajihara K, Ishii S, Ikegame K, et al. Safety and
feasibility of physical therapy in cytopenic patients during allogeneic
haematopoietic stem cell transplantation. Eur J Cancer Care 2013; 22:289-99.
 ACCEPTED MANUSCRIPT

Table 1. Common causes of pancytopenia

Impaired production Peripheral Impaired production and

destruction peripheral destruction

Aplastic anemia – acquired and Autoimmune Paroxysmal nocturnal

T
congenital hemolytic hemoglobinuria

IP
pancytopenia

CR
Bone marrow infiltrating SLE

disorders Splenic
Drugs

US
sequestration
- Malignancy
Leukemia
AN
- Primary and autoimmune

myelofibrosis Hemophagocytic
M

- Granulomatous disorders lymphohistiocytosis (HLH)

ED

- Metabolic disorders
Transfusion-associated Graft-
PT

Nutritional deficiencies versus-host disease

CE

- Vitamin B12 Infections

AC

- Folic acid

- Copper

Myelodysplastic syndrome
 ACCEPTED MANUSCRIPT

Table 2. Inheritable bone marrow failure syndromes.

Congenital Characteristic Gene affected Laboratory

syndrome features finding

Fanconi’s Anemia Predisposition to Multiple FA Increased

T
MDS/AML squamous genes from chromosome

IP
cell cancers FANCA to fragility

CR
VACTERL-H FANCQ

deformities, café-au-

lait lesions,
US
AN
microcephaly,

developmental delay
M

Dyskeratosis Reticulated skin Multiple genes Shortened

ED

congenita hyperpigmentation, regulating telomeres in flow

PT

nail dystrophy, telomerase cytometry

mucosal leukoplakia complex and

CE

shelterin protein
AC

Shwachman –
Shwachman- Pancreatic Abnormal
Bodian –
Diamond dysfunction, various pancreatic
Diamond
syndrome skeletal deformities, functions
Syndrome
(SBDS)
recurrent infection,

myelodysplasia and
 ACCEPTED MANUSCRIPT

AML

GATA2 associated Familial MDS/AML, Monocytopenia, B

GATA2 gene
syndromes increased and NK cell

susceptibility to non- lymphocytopenia

tuberculosis

T
mycobacteria and

IP
viral infections

CR
Amegakaryocytic Absence of Myeloproliferati Elevated serum

US
thrombocytopenia megakaryocytes on ve leukemia thrombopoietin

bone marrow virus ( MPL)

AN
MPL undetectable
oncogene
in flow cytometry
M

VACTERL-H: Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal

ED

fistula and/or Esophageal atresia, Renal & Radial anomalies and Limb defects –
PT

Hydrocephalus
CE
AC